WO2019179515A1 - 受体抑制剂、包含其的药物组合物及其用途 - Google Patents
受体抑制剂、包含其的药物组合物及其用途 Download PDFInfo
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- WO2019179515A1 WO2019179515A1 PCT/CN2019/079226 CN2019079226W WO2019179515A1 WO 2019179515 A1 WO2019179515 A1 WO 2019179515A1 CN 2019079226 W CN2019079226 W CN 2019079226W WO 2019179515 A1 WO2019179515 A1 WO 2019179515A1
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- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
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- 239000008159 sesame oil Substances 0.000 description 1
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
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- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
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- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the present invention relates to angiotensin II (AT 2) type 2 receptor inhibitors, pharmaceutical compositions containing them and their use for the prevention or treatment of AT 2 receptor mediated disorder or symptoms associated therewith.
- AT 2 angiotensin II
- A-II receptor subtypes Two angiotensin II (A-II) receptor subtypes, the AT 1 and AT 2 subtypes, are known. In the rat brain, the A-II receptor is predominantly the AT 2 subtype. AT 2 specific inhibitors are valuable in the treatment of various cerebrovascular, cognitive and central nervous system (CNS) diseases. In addition, AT 2 receptors are found in neuronal tumor cells and transformed human neural cells.
- CNS central nervous system
- the AT 2 receptor is also involved in the differentiation and regeneration of neuronal tissue and the maintenance of bone.
- Impaired nerve conduction velocity is also associated with nerve damage and has been implicated in peripheral neuropathy, carpal tunnel syndrome, ulnar neuropathy, Guillain-Barré syndrome, facial scapula muscle atrophy, and disc herniation. Impaired nerve conduction velocity can result in impaired reflex response and peripheral sensory changes, such as paresthesia and, in some cases, pain.
- AT 2 receptor inhibitor it has been shown to be able to restore nerve conduction velocity.
- AT 2 receptor inhibitor has been shown to have anti-proliferative activity.
- Osteoporosis is a significant problem in older populations, especially in postmenopausal women.
- Current therapies for osteoporosis rely on calcium supplementation.
- control of bone formation and bone resorption is complex. It has been shown that AT 2 receptor inhibitors are capable of increasing bone mass.
- the AT 2 receptor also has an effect of regulating neuronal regrowth and the related effects of AT 2 receptor inhibitors on reducing extracellular growth, suggesting that AT 2 receptor inhibitors can be used as suitable therapeutic agents for diseases characterized by abnormal nerve regeneration. .
- the AT 2 receptor is also present in the female reproductive organs of mammals, including the uterus and ovaries. The role of angiotensin II in the process leading to ovulation has been reported.
- the present invention provides compounds useful as AT 2 receptor inhibitors having excellent inhibitory activity against AT 2 receptors, better physicochemical properties (e.g., solubility, physical and/or chemical stability), improved drug metabolism More excellent properties such as kinetic properties (eg improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window). More specifically, the compounds of the present invention have selective inhibitory activity against the AT 2 receptor relative to the AT 1 receptor.
- physicochemical properties e.g., solubility, physical and/or chemical stability
- improved drug metabolism More excellent properties such as kinetic properties (eg improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window). More specifically, the compounds of the present invention have selective inhibitory activity against the AT 2 receptor relative to the AT 1 receptor.
- One aspect of the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein
- the compound has the structure of formula (I) or formula (I'):
- a ring C atom at a position marked with a symbol "*" is connected to a ring C atom at a position marked with a symbol "#" or "##" through a U group;
- X 3 is CR 10 or N
- R is:
- R 1a , R 1b together with the X 1 to which they are attached form a saturated or partially unsaturated C 3-10 cycloalkyl, a saturated or partially unsaturated 3-10 membered heterocyclyl, a C 6-10 aryl or 5-14 membered heteroaryl;
- X 4 is a direct key
- R 1a is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkyne Any of CH 2 in the group is optionally replaced by O or S; a saturated or partially unsaturated C 3-10 cycloalkyl; a saturated or partially unsaturated 3-10 membered heterocyclyl; C 6-10 aryl; 5-14 membered heteroaryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; -C 1-6 alkylene-saturated or partially unsaturated 3-10 membered a cyclic group; -C 1-6 alkylene-C 6-10 aryl; and -C 1-6 alkylene-(5-14 membered heteroaryl);
- R 1b is absent or selected from: H and R 1a ;
- X 1 does not exist or is CR 10 or N;
- R 1b together with X 1 form a saturated or partially unsaturated divalent C 3-10 cycloalkyl group or a saturated or partially unsaturated divalent 3-10 membered heterocyclic group;
- the condition is: when X 4 is a direct bond, X 1 is CR 10 or N;
- R 1a and R 1b are each independently a C 3-10 cycloalkyl group, a 3-10 membered heterocyclic group, a C 6-10 aryl group or a 5-14 membered heteroaryl group, and the available ring atoms on R 1a are available by the Y group attached a ring atom R 1b, R 1a and R 1b so that they are attached to form an optionally substituted X 1 comprises three or more saturated or partially unsaturated cyclic fused ring system;
- X 1 is CR 10 or N
- R 9 is selected from the group consisting of: H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
- R’ is:
- R 2a, R 2b and X 2 which they are attached together form a saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl, or 5 -14-membered heteroaryl;
- X 5 is a direct key
- R 2a is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, wherein the C 1-8 alkyl, C 2-8 alkenyl and C 2-8 any alkynyl group optionally substituted with a CH 2 O, or S; a saturated or partially unsaturated C 3-10 cycloalkyl; a saturated or partially unsaturated 3-10 membered heterocyclyl; C 6-10 aryl group ; 5-14 membered heteroaryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; -C 1-6 alkylene-saturated or partially unsaturated 3-10 a heterocyclic group; -C 1-6 alkylene-C 6-10 aryl; and -C 1-6 alkylene-(5-14 membered heteroaryl);
- R 2b is absent or selected from: H and R 2a ;
- X 2 does not exist or is CR 10 or N;
- R 2b together with X 2 forms a saturated or partially unsaturated divalent C 3-10 cycloalkyl group or a saturated or partially unsaturated divalent 3-10 membered heterocyclic group;
- the condition is: when X 5 is a direct bond, X 2 is CR 10 or N;
- R 2a and R 2b are each independently a C 3-10 cycloalkyl group, a 3-10 membered heterocyclic group, a C 6-10 aryl group or a 5-14 membered heteroaryl group, and a ring atom available on R 2a the Z groups attached to the available ring atom on R 2b, R 2a and R 2b so to which they are attached form an optionally substituted X 2 together contain 3 or more saturated or partially unsaturated cyclic fused ring system ;
- X 2 is CR 10 or N
- R 11 and R 12 at each occurrence is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl -O-, C 1 -6 alkyl-S-, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
- h and k are each independently 1, 2, 3, 4, 5 or 6;
- alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally 1, 2, 3 at each occurrence.
- x 0, 1 or 2 independently each time it appears;
- Each occurrence of y and z is independently 1 or 2.
- compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N- An oxide, an isotopically labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation or a gaseous formulation.
- Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or Use of a medicament or a pharmaceutical composition of the invention in the manufacture of a medicament for use as an AT2 receptor inhibitor.
- Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A pharmaceutical or a pharmaceutical composition of the invention for use as an AT 2 receptor inhibitor.
- Acceptable compound aspect of the invention provides methods of preventing or treating AT 2 receptor-mediated disorder or symptoms associated therewith, the method according to the present invention comprises administering to an individual in need thereof an effective amount of a pharmaceutically acceptable, or Salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
- Another aspect of the present invention to provide female patients adjustment associated with reproductive function AT 2 receptor the method comprising requires a compound of the present invention is administered to a subject an effective amount thereof, or a pharmaceutically acceptable salt thereof, Esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
- Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or drug, or a pharmaceutical composition of the present invention in the preparation for the prevention or treatment of aT 2 receptor-mediated disorder or symptoms associated therewith medicament.
- Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or Use of a medicament or a pharmaceutical composition of the invention in the manufacture of a medicament for modulating reproductive function associated with AT 2 receptors in a female patient.
- Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A medicament or a pharmaceutical composition of the invention for use in preventing or treating an AT 2 receptor mediated disorder or a condition associated therewith.
- Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A medicament or a pharmaceutical composition of the invention for use in regulating the reproductive function associated with the AT 2 receptor in a female patient.
- alkylene denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.
- alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
- an alkyl group has from 1 to 12 carbon atoms, particularly from 1 to 8 (“C 1-8 alkyl”), for example from 1 to 6 carbon atoms (“C 1-6 alkyl”) 1 to 4 carbon atoms (“C 1-4 alkyl”), more particularly 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
- C 1-8 alkyl refers to a linear or branched group of 1 to 8 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3- Methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl , 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc.), which are optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen ( At this point the group is optionally substituted by one or more (such as 1
- C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).
- alkenyl means a linear or branched monovalent hydrocarbon radical comprising one double bond and having 2-8 carbon atoms ("C 2-8 alkenyl", eg "C 2 -6 alkenyl”).
- the alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 -hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, heptenyl and octene base.
- the compounds of the invention may exist in pure E (enthafen) form, pure Z (zusammen) form, or any mixture thereof.
- alkynyl denotes a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6, 7 or 8 carbon atoms, for example ethynyl, 1-propene. Alkynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl Wait.
- cycloalkylene means, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6, such as 5) -6 or 5-7) saturation of a ring carbon atom (ie, "cycloalkylene” and “cycloalkyl") or unsaturated (ie having one or more double bonds and/or triple bonds in the ring) a monocyclic or polycyclic hydrocarbon ring including, but not limited to, (i)cyclopropyl (cyclo), (i)cyclobutyl (cyclo), (sub)cyclopentyl (ring), (sub)cyclohexyl ( Ring), (sub)cycloheptyl (ring), (sub)cyclooctyl (ring), (sub)cyclodecyl (ring), (sub)cyclohexenyl (ring), and the like.
- heterocyclyl means, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6; Or suitably, having from 8 to 10, more suitably having 9 or 10) ring atoms, wherein at least one of the ring atoms is a hetero atom selected from N, O and S and the remaining ring atoms are saturated with C (ie, hetero A cycloalkyl) or partially unsaturated (ie having one or more double and/or triple bonds in the ring) a monocyclic or bicyclic group.
- 3-10 membered (sub)heterocyclic (yl) has 2 to 9 (eg, 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated monocyclic or bicyclic (sub)heterocyclic ring of one or more (e.g., 1, 2, 3 or 4) heteroatoms of O and S.
- monocyclic heterocyclylenes and heterocycles include, but are not limited to, (meth)oxiranyl, (i)aziridine, (az)azetidinyl, Oxetanyl, (i)tetrahydrofuranyl, (di)dioxolinyl, (i)pyrrolidinyl, (i)pyrrolidone, (im)imidazolidinyl, (i)pyrazolidinyl, (i)pyrrolidino, (i)tetrahydropyranyl, (i)piperidinyl, (y)morpholinyl, (di)dithianyl, ( Sub) thiomorpholinyl, (i)piperazinyl or (tri)trithianyl.
- monocyclic heterocyclic rings include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl (e.g., pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl, 1 , 3-dioxolyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl (eg morpholino), thiomorpholinyl, tetrahydrogen -2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,3-oxazinane, 1,3-thiazinane, hexahydro Pyrimidinyl, 1,3-oxathiane, 1,4-oxathiane, 1,3-diazepine Alkyl (1,3-diazepane), 1,4-diazepane
- Bicyclic heteroheterocyclylenes and heterocycles include spiro ring systems, fused (eg, benzofused) systems, or bridged systems.
- the benzofused heterocyclylene group and the heterocyclic ring are referred to as the above-mentioned monocyclic heterocyclylene group and heterocyclic ring group condensed with benzene, for example, having 3 to 6 (suitably having 4-6, more suitably having 5-6) ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms selected from N, O and S and the remaining ring atoms are C saturated Or a partially benzoated benzo derivative of a monocyclic group (ie, "7-10 membered benzo-fused (sub)heterocyclic (yl)”), including, for example, (sub) 2,3-dihydrobenzo Furanyl (sub)1,3-dihydroisobenzofuranyl (sub) 2,3-dihydrobenzo
- (sub)aryl and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
- C 6-10 (sub)aryl” and “C 6-10 aromatic ring” mean an aromatic group containing from 6 to 10 carbon atoms, such as (phenylene)phenyl. (Benzene ring) or (methylene) naphthyl (naphthalene ring).
- the (sub)aryl and aromatic rings are optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
- suitable substituents e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.
- heteroaryl and “heteroaryl” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen) Or sulfur), and, in each case, may be benzo-fused.
- “(sub)heteroaryl” or “heteroaryl” is selected from (i)thienyl, (i)furanyl, (i)pyrrolyl, (i)oxazolyl, (sub)thiazolyl, (i)imidazolyl, (i)pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl), (sub)isoxazolyl, (sub) Isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (i)tetrazolyl (eg 1-tetrazolyl or 5-tetrazolyl), (sub)thiadiazolyl, etc., and Their benzo derivatives; or (i)pyridyl, (i)pyridazinyl, (i)pyrimidinyl, (i)pyrazinyl, (i)triazinyl, and the like, and their benzo derivatives.
- (sub)heteroaryl or “heteroaryl” include pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridyl, imidazopyridinyl and fluorenyl and the like.
- aralkyl as used herein preferably denotes an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein.
- the aryl group can have from 6 to 14 carbon atoms
- the heteroaryl group can have from 5 to 14 ring atoms
- the alkyl group can have from 1 to 6 carbon atoms.
- Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
- halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
- substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present.
- the normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
- substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
- each substituent is selected independently of the other.
- each substituent may be the same or different from another (other) substituent.
- one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
- a point of attachment of a substituent may come from any suitable position of the substituent.
- the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
- suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium (2 H), tritium (3 H)); isotopes of carbon (e.g.
- Chlorine isotope eg 36 Cl
- fluorine isotopes eg 18 F
- iodine isotopes eg 123 I and 125 I
- nitrogen isotopes eg 13 N and 15 N
- oxygen isotopes eg 15 O
- phosphorus isotope eg 32 P
- sulfur isotope eg 35 S
- Certain isotopically-labeled compounds of the invention e.g., those incorporating radioisotopes
- are useful in drug and/or substrate tissue distribution studies e.g., assays).
- the radioisotope ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
- Substitution with positron emitting isotopes eg, 11 C, 18 F, 15 O, and 13 N
- PET positron emission tomography
- Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations.
- the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
- stereoisomer denotes an isomer formed by at least one asymmetric center.
- a compound having one or more (eg, one, two, three or four) asymmetric centers it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers.
- Specific individual molecules can also exist as geometric isomers (cis/trans).
- the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
- tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
- Solid lines can be used in this article Solid wedge Virtual wedge
- the carbon-carbon bonds of the compounds of the invention are depicted.
- the use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
- the use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown.
- solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
- the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
- the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
- the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
- compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
- pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof
- the compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug.
- a “compound of the invention” it is also intended to encompass the various derivative forms described above for the compound.
- the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
- Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, sea benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid
- Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.
- esters means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound).
- the compounds of the invention may also be esters per se.
- the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
- a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
- the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
- N-oxides are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed.
- Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
- the synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups.
- MCPBA m-chloroperoxybenzoic acid
- Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines.
- metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
- the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
- prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
- Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
- the invention also encompasses compounds of the invention containing a protecting group.
- a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference.
- the protecting group can be removed at a suitable subsequent stage using methods known in the art.
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled thereof, as described below a compound, metabolite or prodrug.
- a ring C atom at a position marked with a symbol "*" is connected to a ring C atom at a position marked with a symbol "#" or "##" through a U group;
- X 3 is CR 10 or N
- R is:
- X 4 is a direct key
- R 1a is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkyne Any of CH 2 in the group is optionally replaced by O or S; a saturated or partially unsaturated C 3-10 cycloalkyl; a saturated or partially unsaturated 3-10 membered heterocyclyl; C 6-10 aryl; 5-14 membered heteroaryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; -C 1-6 alkylene-saturated or partially unsaturated 3-10 membered cycloalkyl group; -C 1-6 alkylene -C 6-10 aryl; -C 1-6 alkylene and - (5-14 membered heteroaryl);
- R 1b is absent or selected from: H and R 1a ;
- X 1 does not exist or is CR 10 or N;
- R 1b together with X 1 form a saturated or partially unsaturated divalent C 3-10 cycloalkyl group or a saturated or partially unsaturated divalent 3-10 membered heterocyclic group;
- the condition is: when X 4 is a direct bond, X 1 is CR 10 or N;
- R 1a and R 1b are each independently a C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl group, and may be on a ring atom and R 1a
- the available ring atoms on R 1b are linked by a Y group such that R 1a and R 1b together with the X 1 to which they are attached form an optionally substituted saturated or partially unsaturated fused ring system comprising 3 or more rings;
- X 1 is CR 10 or N
- R 9 is selected from the group consisting of: H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
- R’ is:
- R 2a, R 2b and X 2 which they are attached together form a saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl, or 5 -14-membered heteroaryl;
- X 5 is a direct key
- R 2a is selected from: C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 Any CH 2 in the alkynyl group is optionally replaced by O or S; a saturated or partially unsaturated C 3-10 cycloalkyl group; a saturated or partially unsaturated 3-10 membered heterocyclic group; C 6-10 aryl ; 5-14 membered heteroaryl; -C 1-6 alkylene-saturated or partially unsaturated C 3-10 cycloalkyl; -C 1-6 alkylene-saturated or partially unsaturated 3-10 a heterocyclic group; -C 1-6 alkylene-C 6-10 aryl; and -C 1-6 alkylene-(5-14 membered heteroaryl);
- R 2b is absent or selected from: H and R 2a ;
- X 2 does not exist or is CR 10 or N;
- R 2b together with X 2 forms a saturated or partially unsaturated divalent C 3-10 cycloalkyl group or a saturated or partially unsaturated divalent 3-10 membered heterocyclic group;
- the condition is: when X 5 is a direct bond, X 2 is CR 10 or N;
- R 2a and R 2b are each independently a C 3-10 cycloalkyl group, a 3-10 membered heterocyclic group, a C 6-10 aryl group or a 5-14 membered heteroaryl group, and a ring atom available on R 2a
- the ring atoms available on R 2b are bonded through a Z group such that R 2a and R 2b together with the X 2 to which they are attached form an optionally substituted saturated or partially unsaturated fused ring system comprising 3 or more rings.
- X 2 is CR 10 or N
- R 11 and R 12 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1 at each occurrence.
- -6 alkyl-S- C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
- h and k are each independently 1, 2, 3, 4, 5 or 6;
- alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally 1, 2, 3 at each occurrence.
- x 0, 1 or 2 independently each time it appears;
- Each occurrence of y and z is independently 1 or 2.
- R 3 is -P(O)(OR 11 )(OR 12 ), preferably -P(O)(OH) 2 , -P(O)(OH)(OC 1-6 alkyl Or -P(O)(OC 1-6 alkyl) 2 , preferably -P(O)(OH) 2 , -P(O)(OH)(OC 1-3 alkyl) or -P( O) (OC 1-3 alkyl) 2 , more preferably -P(O)(OH) 2 , -P(O)(OH)(OCH 3 ) or -P(O)(OH)(OCH 2 CH 3 ).
- R 11 and R 12 are each independently selected from H, C 1-4 alkyl, C 5-7 cycloalkyl, 5-7 membered monocyclic heterocyclyl, phenyl, 5 at each occurrence.
- a -6 membered heteroaryl preferably selected from the group consisting of H and C 1-4 alkyl; each of said alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl groups is optionally 1, 2, 3 or more Multiple R 13 substitutions.
- alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl and heteroaryl are further optionally substituted by 1, 2, 3 or more substituents independently selected from the group consisting of: F, Cl, Br, I, OH, oxo, amino, cyano, nitro, C 1-4 alkyl, halo C 1-4 alkyl, C 5-6 cycloalkyl, 5-7 membered monocyclic Heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably F, Cl, OH, amino, cyano, nitro, C 1-4 alkyl and halo C 1-4 alkyl.
- each occurrence of R 11 and R 12 is independently a C 1-6 alkyl group optionally substituted by 1, 2, 3 or more halogens a C 1-3 alkyl group optionally substituted by 1, 2 or 3 F or Cl, more preferably a methyl group, an ethyl group, a propyl group or an isopropyl group, more preferably a methyl group;
- C 1-6 alkyl substituted by C 3-10 cycloalkyl or 3-10 membered heterocyclyl group preferably C 1-6 alkyl substituted by a C 3-7 cycloalkyl or a 4-7 membered heterocyclic hydrocarbon group, preferably a C 5-7 cycloalkyl or a 5-7 membered monocyclic heterocyclic group substituted by C 1-3 alkyl, wherein the alkyl group is optionally substituted by 1, 2, 3 or more OH or halogen, preferably It is optionally substituted with 1, 2 or 3 OH, F or Cl.
- R is:
- R 1a , R 1b together with the X 1 to which they are attached form a group selected from the group consisting of 1 , 2, 3 or more R 13 substituted: C 5-7 cycloalkyl; 10-membered heterocyclyl; C 6-10 aryl group; and a 5-10 membered heteroaryl; and
- X 4 is a direct key.
- the compound of item 10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein The compound has the structure of the formula (I-1) or the formula (I'-1):
- R 1a , R 1b together with the X 1 to which they are attached form a group selected from the group consisting of 1 , 2, 3 or more R 13 substituted: C 5-7 cycloalkyl; a 6 or 7 membered monocyclic heterocyclic group; and a phenyl group.
- R 1a , R 1b together with the X 1 to which they are attached form a group selected from the group consisting of 1 , 2, 3 or more R 13 substituted: 5-10 membered heteroaryl ( For example 5-6 membered heteroaryl);
- the heteroaryl group is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fluorenyl, isoindole , carbazolyl, benzimidazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyrimidine And pyrazolopyridinyl, imidazopyridinyl, fluorenyl; preferably selected from pyrazolyl, pyrimidinyl, quinazolinyl and pyrazolopyrimidinyl; more preferably selected from
- R 13 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, OH, amino, cyano, C 1-4 alkyl and phenyl C 1-4 Alkyl, C 6-10 aryl or -C 1-4 alkylene-R 11 ; and wherein R 11 is selected from C 5-7 cycloalkyl, 5-7 membered monocyclic heterocyclyl, phenyl and 5- 6-membered heteroaryl;
- R 13 is C 1-4 alkyl, phenyl or optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, C 1-4 alkyl and phenyl -C 1-4 alkylene-phenyl.
- R 13 is phenyl or fluorophenyl (preferably ).
- R 13 is methyl or -CH 2 -phenyl.
- R is:
- R 1a is a group selected from the group consisting of 1, 2, 3 or more R 13 substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Base, C 3-7 cycloalkyl, 4-7 membered monocyclic heterocyclic group, 8-10 membered benzofused heterocyclic group, phenyl group, 5-10 membered heteroaryl group, -C 1-3 alkylene group -C 3-7 cycloalkyl, -C 1-3 alkylene - (monocyclic 5-7 membered heterocyclyl), - C 1-3 alkylene group - (8-10 membered benzo-fused heterocyclic group ), -C 1-3 alkylene phenyl and -C 1-3 alkylene-(5-10 membered heteroaryl);
- R 1b is absent or is selected from H and R 1a .
- R 1a is a group selected from the group consisting of 1, 2, 3 or more R 13 substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne a C 5-7 cycloalkyl group, a 4-7 membered monocyclic heterocyclic group (including a 5, 6 or 7 membered monocyclic heterocyclic group), a 8-10 membered benzofused heterocyclic group, a phenyl group, 5- 10-membered heteroaryl (including 5-6 membered heteroaryl), -C 1-3 alkylene-C 3-7 cycloalkyl, -C 1-3 alkylene-(5-7 membered monocyclic heterocycle) Base), -C 1-3 alkylene phenyl and -C 1-3 alkylene-(5-6 membered heteroaryl).
- R 1a is a group selected from the group consisting of an optionally substituted C 3-7 cycloalkyl group, an optionally substituted 4-7 membered monocyclic heterocyclic group, and an optionally substituted 8-10 membered benzofused heterocyclic group.
- R 1a is a group selected from the group consisting of an optionally substituted C 3-7 cycloalkyl group, an optionally substituted 4-7 membered monocyclic heterocyclic group, and an optionally substituted 8-10 membered benzo fused group.
- Heterocyclic group optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, -C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), -C 1-3 Alkylene-(optionally substituted 5-7 membered monocyclic heterocyclic group), -C 1-3 alkylene group (optionally substituted 8-10 membered benzofused heterocyclic group), optionally Substituted C 1-3 alkylene-optionally substituted phenyl, and -C 1-3 alkylene-(optionally substituted 5-10 membered heteroaryl);
- R 1b does not exist
- R 1a is a group selected from the group consisting of an optionally substituted 5, 6 or 7 membered monocyclic heterocyclic group, an optionally substituted phenyl group, and an optionally substituted C 1-3 alkylene group - optionally substituted Phenyl group;
- cycloalkyl group is, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;
- heteroaryl group an optionally substituted 5-10 membered heteroaryl group, and a -C 1-3 alkylene group (optionally substituted 5-10 membered heteroaryl group), wherein the heteroaryl group is, for example and
- R 13 is selected from the group consisting of: halogen, OH, -NR 11 R 12 , cyano and C 1-4 alkyl; and optionally 1, 2 or 3 independently selected from halogen, OH, - a phenyl group substituted with a substituent of NR 11 R 12 , a cyano group and a C 1-4 alkyl group, a 5-, 6- or 7-membered monocyclic heterocyclic group and a 5-6 membered heteroaryl group, and wherein each of R 11 and R 12 Independently selected from H and C 1-4 alkyl (preferably methyl);
- R 13 is selected from the group consisting of: F, Cl, Br, -N(CH 3 ) 2 and C 1-4 alkyl; and optionally 1, 2 or 3 independently selected from F, Cl, Br and A substituted phenyl group of a C 1-4 alkyl group, a 5-7 membered monocyclic heterocyclic group (for example) And 5-6 membered heteroaryl (for example) ).
- R 1a is selected from:
- R 1a is selected from C 2-6 alkenyl (preferably vinyl, 1-propenyl or 2-propenyl) and C 2-6 alkynyl optionally substituted by 1, 2, 3 or more R 13 ( Preferred is ethynyl, 1-propynyl or 2-propynyl);
- R 13 is selected from phenyl and 5-6 membered heteroaryl optionally substituted by 1, 2 or 3, independently selected from halo, OH, amino, cyano and C 1-4 alkyl;
- R 13 is phenyl or pyridyl optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and Br.
- R 1a is selected from C 2-6 alkenyl (e.g., ethenyl, 1-propenyl or 2-propenyl) and C 2-6 alkynyl optionally substituted by 1, 2, 3 or more R 13 ( For example, ethynyl, 1-propynyl or 2-propynyl); and/or
- R 1b is selected from C 1-4 alkyl optionally substituted by 1, 2, 3 or more R 13 .
- R 13 is selected from C 1-4 alkyl optionally substituted by 1, 2 or 3 independently selected from the group consisting of halogen, OH, amino, cyano and C 1-4 alkyl, phenyl and 5-6 membered Aryl;
- R 13 is C 1-4 alkyl or phenyl optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and Br;
- R 13 is C 1-4 alkyl (eg methyl, ethyl, propyl, isopropyl or tert-butyl) or optionally 1, 2 or 3 independently selected from F, Cl a phenyl group substituted with a substituent of Br.
- R 1a is and / or
- R 1b is methyl, ethyl, n-propyl or isopropyl.
- R 1a is a group selected from the group consisting of an optionally substituted C 3-7 cycloalkyl group, an optionally substituted 4-7 membered monocyclic heterocyclic group, and an optionally substituted 8-10 membered benzofused heterocyclic group.
- R 1a is a group selected from the group consisting of an optionally substituted C 3-7 cycloalkyl group, an optionally substituted 4-7 membered monocyclic heterocyclic group, and an optionally substituted 8-10 membered benzo fused group.
- Heterocyclic group optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, -C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), -C 1-3 Alkylene-(optionally substituted 5-7 membered monocyclic heterocyclic group), -C 1-3 alkylene group (optionally substituted 8-10 membered benzofused heterocyclic group), -C 1 a -3 alkylene-optionally substituted phenyl group, and -C 1-3 alkylene group - (optionally substituted 5-10 membered heteroaryl group);
- cyclic hydrocarbon group being, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
- R 13 is selected from the group consisting of: halogen, -OR 11 (preferably, R 11 is a C 1-6 alkyl group optionally substituted by 1, 2, 3 or more halogens, more preferably optionally 1 , 2 or 3 F or Cl substituted C 1-3 alkyl), -NR 11 R 12 , cyano and C 3-7 cycloalkyl, and optionally substituted by 1, 2, 3 or more halogens C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, and wherein R 11 and R 12 are each independently selected from H and C 1-4 alkyl (preferably methyl);
- R 13 is selected from the group consisting of: F, Cl, Br, OH, -OC 1-4 alkyl, -N(C 1-4 alkyl) 2 , cyano, C 3-7 cycloalkyl, C 2-4 Alkenyl and C 2-4 alkynyl, and C 1-4 alkyl optionally substituted by 1, 2, 3 or more F, Cl or Br;
- R 13 is selected from the group consisting of: F, Cl, Br, -OCH 3 , -N(CH 3 ) 2 , cyano, cyclopropyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 2-propynyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl and CF 3 ;
- R 13 is as defined in item 9.
- R 1b is a group selected from the group consisting of H, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted phenyl, optionally substituted C 1-3 alkylene-(optionally substituted C 3-7 cycloalkyl), and optionally substituted C 1-3 alkylene-optionally substituted phenyl;
- R 1b is a group selected from the group consisting of H, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted phenyl, -C 1-3 An alkyl-(optionally substituted C 3-7 cycloalkyl), and a -C 1-3 alkylene-optionally substituted phenyl;
- R 1b is a group selected from the group consisting of H, phenyl
- An optionally substituted C 1-4 alkyl group such as methyl, ethyl or isopropyl
- C 3-7 cycloalkyl group and a -C 1-3 alkylene group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group; as well as
- R 13 is preferably selected from the group consisting of halogen and C 1-4 alkyl, more preferably selected from the group consisting of F, Cl, Br and methyl.
- R 1b is selected from the group consisting of: H, methyl, ethyl, isopropyl, CF 3 CH 2 , cyclopropyl, Phenyl,
- R 2a is selected from the group consisting of: an optionally substituted phenyl group, and an optionally substituted C 1-3 alkylene group - an optionally substituted phenyl group;
- R 2a is selected from the group consisting of: an optionally substituted phenyl group, and a -C 1-3 alkylene group - an optionally substituted phenyl group; and/or
- R 2b is selected from the group consisting of: an optionally substituted C 1-4 alkyl group, an optionally substituted phenyl group, and an optionally substituted C 1-3 alkylene group - an optionally substituted phenyl group;
- R 2b is selected from the group consisting of: C 1-4 alkyl, optionally substituted phenyl, and -C 1-3 alkylene-optionally substituted phenyl;
- R 13 is selected from the group consisting of F, Cl, Br and -OCH 3 .
- R 2a is selected from: phenyl, and / or
- R 2b is selected from the group consisting of methyl, phenyl,
- R 1a , R 1b , X 1 , X 4 , R 2a , R 2b , X 2 , R 3 , R 4 , h and k are as defined in any one of items 43 to 54.
- R is:
- R 1a is a group selected from the group consisting of 1, 2, 3 or more R 13 substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne , C 5-7 cycloalkyl, 5, 6 or 7 membered monocyclic heterocyclic group, 8-10 membered benzofused heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -C 1-3 alkyl -C 3-7 cycloalkyl, -C 1-3 alkylene - (5-7 membered monocyclic heterocyclic group), - C 1-3 alkylphenyl and -C 1-3 alkylene alkylene -(5-6 membered heteroaryl);
- R 1b together with X 1 form a divalent C 5-7 cycloalkyl group, or a 5, 6 or 7 membered divalent monocyclic heterocyclic group;
- R 1a is a phenyl group
- R 1b is formed together with X 1
- R 13 is selected from the group consisting of: C 1-4 alkyl-O-; halogen (which includes F, Cl, Br, and I); and optionally 1, 2 or 3 C 1-4 alkyl or phenyl substituted independently of a substituent selected from halogen.
- the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1 -hexyl, 1-heptyl and 1-octyl;
- the alkenyl group is selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl and 2-hexenyl;
- the alkynyl group is selected from the group consisting of: ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentyne Base, 2-hexynyl and 3-hexynyl;
- the -C 1-3 alkylene phenyl group is selected from the group consisting of benzyl and phenethyl;
- the cyclic hydrocarbon group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
- the monocyclic heterocyclic group is selected from the group consisting of: tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl (for example pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl, 1,3-dioxo Heterocyclopentyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl (eg morpholino), thiomorpholinyl, tetrahydro-2H-pyran Base, tetrahydro-2H-thiopyranyl, 1,3-oxazinane, 1,3-thiazinane, hexahydropyrimidinyl, 1, 3-oxathiane, 1,4-oxathiane, 1,3-diazepanyl (1, 3-diazepane), 1,4-diazepane, 1,3
- the heteroaryl group is selected from the group consisting of: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; or
- the benzofused heterocyclic group is selected from the group consisting of:
- R is:
- the optionally substituted saturated or partially unsaturated fused ring system comprising 3 or more rings formed by R 1a and R 1b together with the X 1 to which they are attached has the structure of the following formula (a):
- Ring A and Ring B are each independently C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl, preferably C 5-7 cycloalkyl (eg, ring) Pentyl or cyclohexyl), 5-7 membered monocyclic heterocyclic group, phenyl or 5-6 membered heteroaryl;
- the fused ring system has the structure of formula (1) or formula (2):
- R 5a and R 5b are each independently R 10 at each occurrence;
- R 7 does not exist or is R 10 ;
- n are each independently 0, 1, 2 or 3 at each occurrence.
- the group of the formula (1) has the following structure:
- the group of the formula (2) has the following structure:
- R is:
- R 9 is selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 5-7 cycloalkyl, 5-7 membered monocyclic heterocyclic, phenyl, 5- 6-membered heteroaryl and phenyl-C 1-6 alkylene-, preferably selected from: H, C 1-4 alkyl (which includes methyl, ethyl, n-propyl, isopropyl, n-butyl) , isobutyl, sec-butyl and tert-butyl), C 2-4 alkenyl (which includes vinyl, 1-propenyl, 2-propenyl, 2-butenyl and 3-butenyl) C 2-4 alkynyl (which includes ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl), phenyl and phenyl-C 1-4 alkylene- (
- alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl groups are optionally substituted by 1, 2, 3 or more R 13 ;
- R 13 is as defined in any one of items 1 to 9;
- each occurrence of R 13 is independently selected from the group consisting of: halogen (which includes F, Cl, Br, and I); OH; amino; cyano; nitro; and optionally 1, 2, 3 or more. a plurality of C 1-6 alkyl groups (including C 1-4 alkyl groups) independently substituted with a substituent selected from halogen (which includes F, Cl, Br, and I), OH, amino, cyano, nitro, and phenyl groups For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl) and C 6-10 aryl (for example phenyl).
- halogen which includes F, Cl, Br, and I
- OH amino
- cyano nitro
- phenyl groups For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobuty
- R 2a , R 2b together with the X 2 to which they are attached form a group selected from the group consisting of 1, 2, 3 or more R 13 substituted: C 5-7 cycloalkyl; a 6- or 7-membered monocyclic heterocyclic group; a phenyl group; and a 5-6 membered heteroaryl group;
- X 5 is a direct key.
- R 2a is a group selected from the group consisting of 1, 2, 3 or more R 13 substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne , C 5-7 cycloalkyl, 5, 6 or 7 membered monocyclic heterocyclic group, 8-10 membered benzofused heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -C 1-3 alkyl -C 3-7 cycloalkyl, -C 1-3 alkylene - (5-7 membered monocyclic heterocyclic group), - C 1-3 alkylphenyl and -C 1-3 alkylene alkylene -(5-6 membered heteroaryl);
- R 2b is absent or selected from H and R 2a .
- R 2a is a group selected from the group consisting of an optionally substituted 5, 6 or 7 membered monocyclic heterocyclic group, an optionally substituted phenyl group, and an optionally substituted C 1-3 alkylene group - optionally substituted a phenyl group, wherein the substituent optionally present is 1, 2, 3 or more R 13 ;
- R 2b does not exist
- R 2a is a group selected from the group consisting of 1, 2, 3 or more R 13 substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne , C 5-7 cycloalkyl, 5, 6 or 7 membered monocyclic heterocyclic group, 8-10 membered benzofused heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -C 1-3 alkyl -C 3-7 cycloalkyl, -C 1-3 alkylene - (monocyclic 5-7 membered heterocyclyl), - C 1-3 alkylphenyl and -C 1-3 alkylene alkylene -(5-6 membered heteroaryl);
- R 2b together with X 2 forms a divalent C 5-7 cycloalkyl group, or a 5, 6 or 7 membered divalent monocyclic heterocyclic group;
- R 13 is selected from: C 1-4 alkyl-O-; halogen (which includes F, Cl, Br, and I); and optionally 1, 2 or 3 independently selected from halogen Substituent substituted C 1-4 alkyl or phenyl.
- the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1 -hexyl, 1-heptyl and 1-octyl;
- the alkenyl group is selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, and 2-hexenyl;
- the alkynyl group is selected from the group consisting of: ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentyne Base, 2-hexynyl and 3-hexynyl;
- the cyclic hydrocarbon group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
- the monocyclic heterocyclic group is selected from the group consisting of: tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl (for example pyrrolidin-1-yl), oxazolidinyl, thiazolidinyl, imidazolidinyl, 1,3-dioxo Heterocyclopentyl, 1,3-oxathiolanyl, piperidinyl, piperazinyl, morpholinyl (eg morpholino), thiomorpholinyl, tetrahydro-2H-pyran Base, tetrahydro-2H-thiopyranyl, 1,3-oxazinane, 1,3-thiazinane, hexahydropyrimidinyl, 1, 3-oxathiane, 1,4-oxathiane, 1,3-diazepanyl (1, 3-diazepane), 1,4-diazepane, 1,3
- the heteroaryl group is selected from the group consisting of: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;
- the benzofused heterocyclic group is selected from the group consisting of: and / or
- the -C 1-3 alkylene phenyl group is selected from the group consisting of benzyl and phenethyl.
- the optionally substituted, saturated or partially unsaturated fused ring system comprising 3 or more rings formed by R 2a and R 2b together with the X 2 to which they are attached has the structure of the following formula (b):
- Ring C and Ring D are each independently C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl, preferably C 5-7 cycloalkyl, 5- a 7-membered monocyclic heterocyclic group, a phenyl group or a 5-6 membered heteroaryl group;
- the fused ring system has the structure of formula (3) or formula (4):
- R 6a and R 6b are each independently R 10 at each occurrence;
- R 8 does not exist or is R 10 ;
- p and q are each independently 0, 1, 2 or 3 at each occurrence.
- the group of the formula (3) has the following structure:
- the group of the formula (4) has the following structure:
- the compound has the structure of formula (I-a) or formula (I'-a):
- the compound has the structure of formula (I-b) or formula (I'-b):
- the compounds of the invention described above have selective inhibitory activity on AT 2 receptor.
- compositions and methods of treatment are provided.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention described above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph thereof, a solvate, an N-oxide, an isotope-labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous state preparation.
- the pharmaceutical composition may further comprise one or more additional therapeutic agents.
- the invention provides a compound of the invention as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled use of a compound, prodrug, or metabolite or a pharmaceutical composition of the invention in the manufacture of medicament as angiotensin II (the aT 2) receptor type 2 inhibitor.
- aT 2 angiotensin II
- the invention provides a compound of the invention as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, prodrug, or metabolite or a pharmaceutical composition of the invention for use as angiotensin II type 2 (AT 2) receptor inhibitors.
- AT 2 angiotensin II type 2
- the invention provides a method of preventing or treating an AT 2 receptor mediated disorder or a condition associated therewith, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention described above Or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof or a pharmaceutical composition of the invention.
- the AT 2 receptor mediated disorder is selected from the group consisting of: a cerebrovascular disorder (which includes cerebral vasospasm and cerebral ischemia); cognitive dysfunction (which includes amnesia, senile dementia, AIDS related) Dementia and Down syndrome; central nervous system diseases or conditions (including addiction such as alcoholism, anxiety, depression or dysthymia, epilepsy, hyperactivity, pain, Parkinson's disease, psychosis, sleep disorders, no Regular autonomic and tardive dyskinesia, schizophrenia, demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis; respiratory diseases (including bronchospasm, asthma and chronic obstructive airways) Disease); neuronal tumor; inflammatory disease (including inflammatory bowel disease and osteoarthritis); gastrointestinal (GI) disease or condition (including ulcerative colitis, Crohn's disease and incontinence); Diastolic blood flow disorders; allergic diseases (including allergies such as eczema, rhinitis, a
- the AT 2 receptor mediated disorder is selected from the group consisting of:
- Neuropathic disorders including primary neuropathy and secondary neuropathy, such as peripheral neuropathy
- symptoms associated with it including hyperesthesia, hyperalgesia, allodynia, spontaneous burning, numbness, weakness, burning pain
- the secondary neuropathy includes: diabetic neuropathy; herpes zoster-associated neuropathy; uremia-associated neuropathy; amyloidosis neuropathy; Neuropathy; hereditary motor and sensory neuropathy; hereditary sensory neuropathy; hereditary sensory and autonomic neuropathy; hereditary neuropathy with ulcer damage; nitrofurantoin neuropathy; sausage-like swelling neuropathy; neuropathy caused by nutritional deficiencies; Neuropathy and complex regional pain syndrome; neuropathy caused by repetitive activities (such as typing or working on assembly lines); antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as Nitrazole and isoniazid), gold compounds, chemotherapeutic drugs (eg vincristine), alcohol
- hyperalgesia conditions such as fibromyalgia, irritable bowel syndrome
- a disorder associated with abnormal nerve regeneration including neuronal hypersensitivity, breast pain, interstitial cystitis, vulvar pain, cancer-induced neuropathy;
- Inflammatory pain which can be attributed to conditions characterized by inflammation (including burns such as chemistry, friction or thermal burns; autoimmune diseases such as rheumatoid arthritis; inflammatory bowel diseases such as Crohn's disease and Colitis; osteoarthritis, carditis, dermatitis, myositis, neuritis and collagen vascular disease);
- Impaired nerve conduction velocity which may be associated with neuropathic disorders (such as peripheral neuropathy) as described above, as well as carpal tunnel syndrome, ulnar neuropathy, Guillain-Barré syndrome, facial scapula muscle atrophy, and disc herniation;
- Cell proliferative disorders including cancer (including leukemia, melanoma, prostate cancer, breast cancer, ovarian cancer, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma, colon cancer, lung cancer); and non-cancerous hyperplasia Symptoms (including skin conditions such as sputum, keloids, psoriasis, sputum disorders, and scar tissue reduction and cosmetic remodeling).
- cancer including leukemia, melanoma, prostate cancer, breast cancer, ovarian cancer, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma, colon cancer, lung cancer
- non-cancerous hyperplasia Symptoms including skin conditions such as sputum, keloids, psoriasis, sputum disorders, and scar tissue reduction and cosmetic remodeling.
- the present invention provides a regulator associated with female patients of reproductive function of AT 2 receptor, the method comprising administering to an individual a compound of the present invention need thereof an effective amount of the above, or Pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
- the reproductive function is selected from the group consisting of a hormonal balance of the menstrual cycle, fertility, and estrus cycle.
- “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
- Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
- the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
- Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
- compositions of the invention may act systemically and/or locally.
- they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration.
- injection for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation
- transdermal administration or by oral, buccal, or oral administration.
- compositions of the invention may be administered in a suitable dosage form.
- the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
- "effective amount" refers to the amount of a compound that, after administration, will relieve to some extent one or more symptoms of the condition being treated.
- the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
- an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
- a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
- the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
- treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.
- “Individual” as used herein includes human or non-human animals.
- Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
- “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
- compositions of the invention may also comprise one or more additional therapeutic or prophylactic agents.
- the structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).
- the chemical shift ( ⁇ ) is given in parts per million (ppm).
- the 1 H NMR measurement was carried out on a Bruker 400 nuclear magnetic instrument.
- the test solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexamethyl dimethyl sulfoxide (DMSO-d 6 ). It is tetramethylsilane (TMS).
- LC-MS was determined on an Agilent LC-MS-1110 LC/MS, Agilent LC-MS-6110 LC/MS, Agilent LC-MS-6120 LC/MS (manufacturer: Agilent) or Shimadzu LC - MS 2020.
- Preparative high performance liquid chromatography was carried out using an MS triggered automated purification system (Waters), Gilson GX-281 (Gilson) or a semi-preparative liquid chromatograph (Innovative Tonghong LC3000 (Ddlsogel, C18, 30 mm x 250 mm 10 ⁇ m)).
- Thin layer chromatography was carried out using a yellow sea brand HSGF 254 (5 ⁇ 20 cm) silica gel plate, and thin layer chromatography was carried out using a silica gel plate of GF 254 (0.4-0.5 nm) manufactured by Yantai.
- the reaction is detected by thin layer chromatography (TLC) or LC-MS using a developing solvent system including a dichloromethane and methanol system, a n-hexane and ethyl acetate system, and a petroleum ether and ethyl acetate system depending on the compound to be separated.
- the developing agent system is adjusted by the difference in polarity (by adjusting the volume ratio of the solvent or adding triethylamine or the like).
- the microwave reaction was carried out using a CEM Discovery Sp (400 W, RT ⁇ 300 ° C) microwave reactor.
- Column chromatography is generally used in the chemical industry 200 ⁇ 300 mesh silica gel as a stationary phase.
- the system of the eluent includes a dichloromethane and methanol system and a n-hexane and ethyl acetate system, and the eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.) get on).
- the temperature of the reaction is room temperature (20 ° C to 30 ° C) as otherwise specified in the examples.
- the reagents used in the examples were purchased from companies such as Aldrich Chemical Company, Shanghai Bied Pharmaceutical Technology Co., Ltd., Beijing Green Kammer Co., Ltd., Suiyuan Technology (Shanghai) Co., Ltd. or Aibo Technology Co., Ltd.
- step 1
- the compound 1 (14.3 g, 0.1 mol) was dissolved in dichloromethane (150 mL), and the starting material trimethyloxonium tetrafluoroborate (16.3 g, 0.11 mol) was added portionwise, and the reaction mixture was allowed to react at room temperature. hour.
- the reaction mixture was cooled with ice water, and the mixture was adjusted to 8.0 with saturated sodium hydrogen carbonate solution, and extracted with dichloromethane (200 mL ⁇ 2).
- the combined organic phase was dried over anhydrous sodium sulfate (100 g) for 30 min, then filtered. Concentrated by pressure.
- the intermediate compound in Table 1 was prepared by a method similar to that described in Intermediate Preparation Example 1.
- the intermediate compound in Table 2 was prepared by a method similar to that described in Intermediate Preparation Example 2.
- step 1
- step 1
- step 1
- step 1
- step 1
- Example 7 (1R, 2R, 5S)-8-((R)-2-(dimethylamino)-3-phenylpropanoyl)-3-(diphenylcarbamoyl)-3,8 -Diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester intermediate (C270-1) and (1R,2R,5S)-8-((S)-2-(dimethylamino)- Preparation of ethyl 3-phenylpropionyl)-3-(diphenylcarbamoyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (C269-1):
- Compound C270-1 was prepared by the above reaction procedure except that SM2 was replaced with SM3.
- step 1
- the compound C34-1 (0.12 g, 0.234 mmol) was dissolved in a mixture of tetrahydrofuran, methanol and water (5 mL/5 mL/5 mL), and sodium hydroxide (47 mg, 1.17 mmol) was added and stirred at room temperature for 5 hours. It is then concentrated to give a crude product. Then, the pH was adjusted to 5.0 with a 3N hydrochloric acid solution, and extracted with ethyl acetate (20 mL ⁇ 3).
- step 1
- Example 10 (1S,3S,4R)-5-(benzylamino)-2-(2,2-diphenylacetyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (C285) and (1S,3S,4R)-5-(benzyl(methyl)amino)-2-(2,2-diphenylacetyl)-2-azabicyclo[2.2.2]octane Preparation of 3-carboxylic acid (C295)
- step 1
- step 1
- step 1
- step 1
- the compound C299-4 (28 mg, 0.052 mmol) was dissolved in methanol (10 ml), water (3 ml), sodium hydroxide (5.12 mg, 0.13 mmol), and the mixture was stirred at 50 ° C for 16 hours.
- Example 16 (1R,2S,5S)-8-((4-allylbenzyl)(methyl)carbamoyl)-3-(diphenylcarbamoyl)-3,8-diaza Heterobicyclo[3.2.1]octane-2-carboxylic acid (C235) and (1R,2S,5S)-3-(diphenylcarbamoyl)-8-(methyl(4-propylbenzyl)amino Preparation of formyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (C236)
- step 1
- AT 1 receptor AT 1 R
- AT 2 receptor AT 2 R
- the inhibitory activity (IC 50 value) of the compound against AT 1 R/AT 2 R was determined by the following procedure:
- NA means not determined.
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Abstract
Description
缩写 | 含义 |
CH 3CN | 乙腈 |
(Boc) 2O | 二碳酸二叔丁酯 |
BTC | 三光气 |
DCM | 二氯甲烷 |
DMSO | 二甲基亚砜 |
TEA | 三乙胺 |
HCl | 盐酸 |
H 2O | 水 |
AcOH | 乙酸 |
MeOH | 甲醇 |
EtOH | 乙醇 |
Na 2CO 3 | 碳酸钠 |
NaOH | 氢氧化钠 |
SOCl 2 | 氯化亚砜 |
TFA | 三氟乙酸 |
THF | 四氢呋喃 |
Me 3O +BF 4 - | 三甲基氧鎓四氟硼酸盐 |
BF 3E t2O | 三氟化硼乙醚 |
PdCl 2(PPh 3) 2 | 双(三苯基膦)二氯化钯 |
Pd/C | 钯碳 |
Claims (94)
- 化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中所述化合物具有式(I)或式(I’)的结构:其中:以符号“*”标记的位置处的环C原子与以符号“#”或“##”标记的位置处的环C原子通过U基团连接;U选自:单键;NR 10;C 1-3亚烷基,其中的1或2个CH 2任选地被独立地选自O、S和NR 10的基团代替;以及C 2-3亚烯基,其中形成C=C双键的任一CH任选地被N代替;X 3为CR 10或N;R为:其中1)R 1a、R 1b与它们所连接的X 1一起形成饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基或5-14元杂芳基;并且X 4为直接的键;或者2)R 1a选自:C 1-8烷基、C 2-8烯基、C 2-8炔基,其中所述C 1-8烷基、C 2-8烯基和C 2-8炔基中的任一CH 2任选地被O或S代替;饱和或部分不饱和的C 3-10环烃基;饱和或部分不饱和的3-10元杂环基;C 6-10芳基;5-14元杂芳基;-C 1-6亚烷基-饱和或部分不饱和的C 3-10环烃基;-C 1-6亚烷基-饱和或部分不饱和的3-10元杂环基;-C 1-6亚烷基-C 6-10芳基;以及-C 1-6亚烷基-(5-14元杂芳基);R 1b不存在或者选自:H和R 1a;X 1不存在或为CR 10或N;或者R 1b与X 1一起形成饱和或部分不饱和的二价C 3-10环烃基或者饱和或部分不饱和的二价3-10元杂环基;X 4选自:直接的键;C(=O);S(=O) y;O;S;NR 10;以及-O-C(=O)-、-S-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-和-NR 10-S(=O) y-,其中O、S、NR 10与X 1连接;优选为直接的键、C(=O)、S(=O) y、-O-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-或-NR 10-S(=O) y-;条件是:当X 4为直接的键时,X 1为CR 10或N;或者3)R 1a和R 1b各自独立地为C 3-10环烃基、3-10元杂环基、C 6-10芳基或5-14元杂芳基,并且R 1a上的可用环原子与R 1b上的可用环原子通过Y基团连接,从而R 1a和R 1b与它们所连接的X 1一起形成任选取代的包含3个或更多个环的饱和或部分不饱和稠环体系;X 1为CR 10或N;X 4选自:C(=O);S(=O) y;O;S;NR 10;以及-O-C(=O)-、-S-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-和-NR 10-S(=O) y-,其中O、S、NR 10与X 1连接;优选为C(=O)或S(=O) y;并且Y选自:单键;NR 10;C 1-3亚烷基,其中的1或2个CH 2任选地被独立地选自O、S和NR 10的基团代替;以及C 2-3亚烯基,其中形成C=C双键的任一CH任选地被N代替;或者其中X 6选自:O;S;NR 10;以及-C(=O)-NR 10-和-S(=O) y-NR 10-,其中C(=O)与S(=O) y与R 9连接;R 9选自:H、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;R’为:其中(1)R 2a、R 2b与它们所连接的X 2一起形成饱和或部分不饱和C 3-10环烃基、饱和或部分不饱和3-10元杂环基、C 6-10芳基或5-14元杂芳基;并且X 5为直接的键;或者(2)R 2a选自:C 1-8烷基、C 2-8烯基、C 2-8炔基,其中所述C 1-8烷基、C 2-8烯基和C 2-8炔基中的任一CH 2任选地被O或S代替;饱和或部分不饱和的C 3-10环烃基;饱和或部分不饱和的3-10元杂环基;C 6-10芳基;5-14元杂芳基;-C 1-6亚烷基-饱和或部分不饱和的C 3-10环烃基;-C 1-6亚烷基-饱和或部分不饱和的3-10元杂环基;-C 1-6亚烷基-C 6-10芳基;以及-C 1-6亚烷基-(5-14元杂芳基);R 2b不存在或者选自:H和R 2a;X 2不存在或为CR 10或N;或者R 2b与X 2一起形成饱和或部分不饱和的二价C 3-10环烃基或者饱和或部分不饱和的二价3-10元杂环基;X 5选自:直接的键;C(=O);S(=O) y;O;S;NR 10;以及-O-C(=O)-、-S-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-和-NR 10-S(=O) y-,其中O、S、NR 10与X 2连接;优选为直接的键、C(=O)、S(=O) y、-O-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-或-NR 10-S(=O) y-;条件是:当X 5为直接的键时,X 2为CR 10或N;或者(3)R 2a和R 2b各自独立地为C 3-10环烃基、3-10元杂环基、C 6-10芳基或5-14元杂芳基,并且R 2a上的可用环原子与R 2b上的可用环原子通过Z基团连接,从而R 2a和R 2b与它们所连接的X 2一起形成任选取代的包含3个或更多个环的饱和或部分不饱和稠环体系;X 2为CR 10或N;X 5选自:C(=O);S(=O) y;O;S;NR 10;以及-O-C(=O)-、-S-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-和-NR 10-S(=O) y-,其中O、S、NR 10与X 2连接;优选为C(=O)或S(=O) y;并且Z选自:单键;NR 10;C 1-3亚烷基,其中的1或2个CH 2任选地被独立地选自O、S和NR 10的基团代替;以及C 2-3亚烯基,其中形成C=C双键的任一CH任选地被N代替;R 3、R 4和R 10各自独立地选自:H、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-OR 11、-SR 11、-P(O)(OR 11)(OR 12)、-OC(=O)R 11、-C(=O)R 11、-C(=O)OR 11、-C(=O)NR 11R 12、-C(=O)NR 11S(=O) yNR 11R 12、-C(=O)NR 11S(=O) yR 12、-S(=O) yR 11、-S(=O) yOR 11、-S(=O) yNR 11R 12、-S(=O) yNR 11S(=O) zOR 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12、-NR 11R 12、-NR 11-C(=O)R 12、-NR 11-C(=O)OR 12、-NR 11-S(=O) y-R 12、-NR 11-C(=O)-NR 11R 12、-C 1-6亚烷基-R 11、-C 1-6亚烷基-OR 11、-C 1-6亚烷基-OC(=O)R 11、-C 1-6亚烷基-C(=O)OR 11、-C 1-6亚烷基-S(=O) xR 11、-C 1-6亚烷基-S(=O) yOR 11、-C 1-6亚烷基-OC(=O)NR 11R 12、-C 1-6亚烷基-C(=O)NR 11R 12、-C 1-6亚烷基-C(=O)NR 11-S(=O) yR 12、-C 1-6亚烷基-NR 11-C(=O)NR 11R 12、-C 1-6亚烷基-OS(=O) yR 11、-C 1-6亚烷基-OS(=O) yNR 11R 12、-C 1-6亚烷基-S(=O) yNR 11R 12、-C 1-6亚烷基-NR 11-S(=O) yNR 11R 12、-C 1-6亚烷基-NR 11R 12和-O-C 1-6亚烷基-NR 11R 12;R 11和R 12在每次出现时各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、C 1-6 烷基-S-、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;h和k各自独立地是1、2、3、4、5或6;上述烷基、亚烷基、烯基、亚烯基、炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被1、2、3或更多个R 13取代,其中所述R 13在每次出现时独立地选自:卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-OR 11、-SR 11、-P(O)R 11R 12、-OC(=O)R 11、-C(=O)R 11、-C(=O)OR 11、-C(=O)NR 11R 12、-C(=O)NR 11S(=O) yNR 11R 12、-C(=O)NR 11S(=O) yR 12、-S(=O) yR 11、-S(=O) yOR 11、-S(=O) yNR 11R 12、-S(=O) yNR 11S(=O) zOR 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12、-NR 11R 12、-NR 11-C(=O)R 12、-NR 11-C(=O)OR 12、-NR 11-S(=O) y-R 12、-NR 11-C(=O)-NR 11R 12、-C 1-6亚烷基-R 11、-C 1-6亚烷基-OR 11、-C 1-6亚烷基-OC(=O)R 11、-C 1-6亚烷基-C(=O)OR 11、-C 1-6亚烷基-S(=O) xR 11、-C 1-6亚烷基-S(=O) yOR 11、-C 1-6亚烷基-OC(=O)NR 11R 12、-C 1-6亚烷基-C(=O)NR 11R 12、-C 1-6亚烷基-C(=O)NR 11-S(=O) yR 12、-C 1-6亚烷基-NR 11-C(=O)NR 11R 12、-C 1-6亚烷基-OS(=O) yR 11、-C 1-6亚烷基-OS(=O) yNR 11R 12、-C 1-6亚烷基-S(=O) yNR 11R 12、-C 1-6亚烷基-NR 11-S(=O) yNR 11R 12、-C 1-6亚烷基-NR 11R 12和-O-C 1-6亚烷基-NR 11R 12,并且其中关于取代基R 13所述的烷基、亚烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被1、2、3或更多个独立地选自下列的取代基取代:卤素、OH、氧代、氨基、氰基、硝基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;并且其中所述杂环基、芳基或杂芳基作为取代基时通过环C原子,或者如果可能,通过环N原子,与分子的其余部分连接;x每次出现时独立地为0、1或2;y和z每次出现时各自独立地为1或2。
- 权利要求1的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中所述化合物具有式(I)的结构:其中:R 3、R 4和R 10各自独立地选自:H、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-OR 11、-SR 11、-OC(=O)R 11、-C(=O)R 11、-C(=O)OR 11、-C(=O)NR 11R 12、-C(=O)NR 11S(=O) yNR 11R 12、-C(=O)NR 11S(=O) yR 12、-S(=O) yR 11、-S(=O) yOR 11、-S(=O) yNR 11R 12、-S(=O) yNR 11S(=O) zOR 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12、-NR 11R 12、-NR 11-C(=O)R 12、-NR 11-C(=O)OR 12、-NR 11-S(=O) y-R 12、-NR 11-C(=O)-NR 11R 12、-C 1-6亚烷基-R 11、-C 1-6亚烷基-OR 11、-C 1-6亚烷基-OC(=O)R 11、-C 1-6亚烷基-C(=O)OR 11、-C 1-6亚烷基-S(=O) xR 11、-C 1-6亚烷基-S(=O) yOR 11、-C 1-6亚烷基-OC(=O)NR 11R 12、-C 1-6亚烷基-C(=O)NR 11R 12、-C 1-6亚烷基-C(=O)NR 11-S(=O) yR 12、-C 1-6亚烷基-NR 11-C(=O)NR 11R 12、-C 1-6亚烷基-OS(=O) yR 11、-C 1-6亚烷基-OS(=O) yNR 11R 12、-C 1-6亚烷基-S(=O) yNR 11R 12、-C 1-6亚烷基-NR 11-S(=O) yNR 11R 12、-C 1-6亚烷基-NR 11R 12和-O-C 1-6亚烷基-NR 11R 12;并且R 13在每次出现时独立地选自:卤素、氰基、硝基、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-OR 11、-SR 11、-OC(=O)R 11、-C(=O)R 11、-C(=O)OR 11、-C(=O)NR 11R 12、-C(=O)NR 11S(=O) yNR 11R 12、-C(=O)NR 11S(=O) yR 12、-S(=O) yR 11、-S(=O) yOR 11、-S(=O) yNR 11R 12、-S(=O) yNR 11S(=O) zOR 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12、-NR 11R 12、-NR 11-C(=O)R 12、-NR 11-C(=O)OR 12、-NR 11-S(=O) y-R 12、-NR 11-C(=O)-NR 11R 12、-C 1-6亚烷基-R 11、-C 1-6亚烷基-OR 11、-C 1-6亚烷基-OC(=O)R 11、-C 1-6亚烷基-C(=O)OR 11、-C 1-6亚烷基-S(=O) xR 11、-C 1-6亚烷基-S(=O) yOR 11、-C 1-6亚烷基-OC(=O)NR 11R 12、-C 1-6亚烷基-C(=O)NR 11R 12、-C 1-6亚烷基-C(=O)NR 11-S(=O) yR 12、-C 1-6亚烷基-NR 11-C(=O)NR 11R 12、-C 1-6亚烷基-OS(=O) yR 11、-C 1-6亚烷基-OS(=O) yNR 11R 12、-C 1-6亚烷基-S(=O) yNR 11R 12、-C 1-6亚烷基-NR 11-S(=O) yNR 11R 12、-C 1-6亚烷基-NR 11R 12和-O-C 1-6亚烷基-NR 11R 12,并且其中关于取代基R 13所述的烷基、亚烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任 选地被1、2、3或更多个独立地选自下列的取代基取代:卤素、OH、氧代、氨基、氰基、硝基、C 1-6烷基、卤代C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基;并且其中所述杂环基、芳基或杂芳基作为取代基时通过环C原子,或者如果可能,通过环N原子,与分子的其余部分连接。
- 权利要求1或2的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中U为:单键、NR 10、O、S、亚甲基、亚乙基、-CH 2-O-、-O-CH 2-、-CH 2-S-、-S-CH 2-、-CH 2-NR 10-、-NR 10-CH 2-、-CH=CH-、-CH=N-或-N=CH-;优选地,U为单键、亚甲基或亚乙基。
- 权利要求1至3中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 3为F、Cl、Br、I、氨基、氰基、硝基、C 1-4烷基、C 5-7环烃基、5-7元单环杂环基、苯基、5-7元杂芳基、-OR 11、-SR 11、-OC(=O)R 11、-C(=O)OR 11、-C(=O)NR 11R 12、-C(=O)NR 11S(=O) yNR 11R 12、-C(=O)NR 11S(=O) yR 12、-S(=O) yOR 11、-S(=O) yNR 11R 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12、-C 1-4亚烷基-OR 11、-C 1-4亚烷基-OC(=O)R 11、-C 1-4亚烷基-C(=O)OR 11、-C 1-4亚烷基-S(=O) yOR 11、-C 1-4亚烷基-OC(=O)NR 11R 12、-C 1-4亚烷基-C(=O)NR 11R 12、-C 1-4亚烷基-OS(=O) yR 11或-C 1-4亚烷基-S(=O) yNR 11R 12;优选为5-6元杂芳基、-C(=O)OR 11、-C(=O)NR 11R 12、-C(=O)NR 11S(=O) yNR 11R 12、-C(=O)NR 11S(=O) yR 12、-S(=O) yOR 11、-S(=O) yNR 11R 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12、-C 1-3亚烷基-OC(=O)R 11、-C 1-3亚烷基-C(=O)OR 11、-C 1-3亚烷基-S(=O) yOR 11、-C 1-3亚烷基-C(=O)NR 11R 12或-C 1-3亚烷基-S(=O) yNR 11R 12;更优选为5-6元杂芳基(例如噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、四唑基如1-四唑基或5-四唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基)、-C(=O)OR 11(例如COOH、COOCH 3或COOCH 2CH 3)、-C(=O)NR 11S(=O) yNR 11R 12(例如 )、-C(=O)NR 11S(=O) yR 12(例如 )、-C(=O)NR 11R 12、-S(=O) yOR 11或-S(=O) yNR 11R 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12(例如 )。
- 权利要求1至3中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 3为-P(O)(OR 11)(OR 12),优选地为-P(O)(OH) 2、-P(O)(OH)(OC 1-6烷基)或-P(O)(OC 1-6烷基) 2,优选地为-P(O)(OH) 2、-P(O)(OH)(OC 1-3烷基)或-P(O)(OC 1-3烷基) 2,更优选地为-P(O)(OH) 2、-P(O)(OH)(OCH 3)或-P(O)(OH)(OCH 2CH 3)。
- 权利要求1至5中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 4和R 10在每次出现时各自独立地为:H、F、Cl、Br、I、氨基、氰基、硝基、C 1-4烷基、C 5-7环烃基、5-7元单环杂环基、苯基、5-6元杂芳基、-OR 11、-SR 11、-OC(=O)R 11、-C(=O)OR 11、-C(=O)NR 11R 12、-C(=O)NR 11S(=O) yNR 11R 12、-C(=O)NR 11S(=O) yR 12、-S(=O) yOR 11、-S(=O) yNR 11R 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12、-C 1-4亚烷基-OR 11、-C 1-4亚烷基-OC(=O)R 11、-C 1-4亚烷基-C(=O)OR 11、-C 1-4亚烷基-S(=O) yOR 11、-C 1-4亚烷基-OC(=O)NR 11R 12、-C 1-4亚烷基-C(=O)NR 11R 12、-C 1-4亚烷基-OS(=O) yR 11或-C 1-4亚烷基-S(=O) yNR 11R 12;优选地为H、F、Cl、Br、I、OH、氨基、氰基、硝基或C 1-4烷基(例如甲基)。
- 权利要求1至6中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 11和R 12在每次出现时各自独立地选自H、C 1-4烷基、C 5-7环烃基、5-7元单环杂环基、苯基、5-6元杂芳基;优选地选自H和C 1-4烷基;所述烷基、环烃基、杂环基、苯基和杂芳基各自任选地被1、2、3或更多个R 13取代。
- 权利要求1至7中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13在每次出现时独立地选自:F、Cl、Br、I、氨基、氰基、硝基、C 1-4烷基、C 5-7环烃基、5-7元单环杂环基、苯基、5-6元杂芳基、C 6-12芳烷基、-OR 11、-SR 11、-OC(=O)R 11、-C(=O)OR 11、-C(=O)NR 11R 12、-C(=O)NR 11S(=O) yNR 11R 12、-C(=O)NR 11S(=O) yR 12、-S(=O) yOR 11、-S(=O) yNR 11R 12、-S(=O) yNR 11C(=O)R 12、-S(=O) yNR 11C(=O)OR 12、-C 1-4亚烷基-R 11、-C 1-4亚烷基-OR 11、-C 1-4亚烷基-OC(=O)R 11、-C 1-4亚烷基-C(=O)OR 11、-C 1-4亚烷基-S(=O) yOR 11、-C 1-4亚烷基-OC(=O)NR 11R 12、-C 1-4亚烷基-C(=O)NR 11R 12、-C 1-4亚烷基-OS(=O) yR 11或-C 1-4亚烷基-S(=O) yNR 11R 12;优选地为F、Cl、Br、I、氨基、氰基、硝基、C 1-4烷基、-OR 11(优选地,R 11为任选地被1、2、3或更多个卤素取代的C 1-6烷基,更优选地为任选地被1、2或3个F或Cl取代的C 1-3烷基)、-SR 11(优选地,R 11为任选地被1、2、3或更多个卤素取代的C 1-6烷基,更优选地为任选地被1、2或3个F或Cl取代的C 1-3烷基)或苯基;并且优选地,其中所述烷基、亚烷基、环烃基、杂环基、苯基和杂芳基进一步任选地被1、2、3或更多个独立地选自下列的取代基取代:F、Cl、Br、I、OH、氧代、氨基、氰基、硝基、C 1-4烷基、卤代C 1-4烷基、C 5-6环烃基、5-7元单环杂环基、苯基和5-6元杂芳基;优选F、Cl、OH、氨基、氰基、硝基、C 1-4烷基和卤代C 1-4烷基。
- 权利要求1和3至7中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13在每次出现时独立地为选自:-P(O)R 11R 12,其中优选地,R 11和R 12在每次出现时各自独立地为任选地被1、2、3或更多个卤素取代的C 1-6烷基,优选任选地被1、2或3个F或Cl取代的C 1-3烷基,更优选甲基、乙基、丙基或异丙基,更优选甲基;和被C 1-6烷基取代的C 3-10环烃基或3-10元杂环基,优选被C 1-6烷基取代的C 3-7环烃基或4-7元杂环基,优选被C 1-3烷基取代的C 5-7环烃基或5-7元单环杂环基,其中所述烷基任选地被1、2、3或更多个OH或卤素取代,优选任选地被1、2或3个OH、F或Cl取代。
- 权利要求10或11的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1a、R 1b与它们所连接的X 1一起形成选自下列的基团,所述基团任选地被1、2、3或更多个R 13取代:C 5-7环烃基;5、6或7元单环杂环基;以及苯基。
- 权利要求10或11的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:R 1a、R 1b与它们所连接的X 1一起形成选自下列的基团,所述基团任选地被1、2、3或更多个R 13取代:5-10元杂芳基(例如5-6元杂芳基);
- 权利要求10至13中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:R 13是任选地被1、2或3个独立地选自卤素、OH、氨基、氰基、C 1-4烷基和苯基的取代基取代的C 1-4烷基、C 6-10芳基或-C 1-4亚烷基-R 11;并且其中R 11选自C 5-7环烃基、5-7元单环杂环基、苯基和5-6元杂芳基;优选地,R 13为任选地被1、2或3个独立地选自F、Cl、Br、C 1-4烷基和苯基的取代基取代的C 1-4烷基、苯基或-C 1-4亚烷基-苯基。
- 权利要求14的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13是任选地被1、2或3个独立地选自C 1-4烷基和苯基的取代基取代的C 1-4烷基或-C 1-4亚烷基-苯基;优选地,R 13是甲基或-CH 2-苯基。
- 权利要求1至9中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R为:其中R 1a为选自下列的基团,所述基团任选地被1、2、3或更多个R 13取代:C 1-6烷基,C 2-6烯基,C 2-6炔基,C 3-7环烃基,4-7元单环杂环基,8-10元苯并稠合杂环基,苯基,5-10元杂芳基,-C 1-3亚烷基-C 3-7环烃基,-C 1-3亚烷基-(5-7元单环杂环基),-C 1-3亚烷基-(8-10元苯并稠合杂环基),-C 1-3亚烷基苯基以及-C 1-3亚烷基-(5-10元杂芳基);并且R 1b不存在或者选自H和R 1a。
- 权利要求18的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1a为选自下列的基团,所述基团任选地被1、2、3或更多个R 13取代:C 1-6烷基,C 2-6烯基,C 2-6炔基,C 5-7环烃基,4-7元单环杂环基(包括5、6或7元单环杂环基),8-10元苯并稠合杂环基,苯基,5-10元杂芳基(包括5-6元杂芳基),-C 1-3亚烷基-C 3-7环烃基,-C 1-3亚烷基-(5-7元单环杂环基),-C 1-3亚烷基苯基以及-C 1-3亚烷基-(5-6元杂芳基)。
- 权利要求1至9和18至19中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1b不存在,且X 1不存在。
- 权利要求20或21的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 4选自:C(=O)、S(=O) y、-O-C(=O)-、-S-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-和-NR 10-S(=O) y-,优选为C(=O)、-O-C(=O)-或-NR 10-C(=O)-。
- 权利要求18和20至22中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1a为选自下列的基团:任选取代的C 3-7环烃基,任选取代的4-7元单环杂环基,任选取代的8-10元苯并稠合杂环基,任选取代的苯基,任选取代的5-10元杂芳基,-任选取代的C 1-3亚烷基-(任选取代的C 3-7环烃基),-任选取代的C 1-3亚烷基-(任选取代的5-7元单环杂环基),-任选取代的C 1-3亚烷基-(任选取代的8-10元苯并稠合杂环基),-任选取代的C 1-3亚烷基-任选取代的苯基,以及-任选取代的C 1-3亚烷基-(任选取代的5-10元杂芳基);优选地,R 1a为选自下列的基团:任选取代的C 3-7环烃基,任选取代的4-7元单环杂环基,任选取代的8-10元苯并稠合杂环基,任选取代的苯基,任选取代的5-10元杂芳基,-C 1-3亚烷基-(任选取代的C 3-7环烃基),-C 1-3亚烷基-(任选取代的5-7元单环杂环基),-C 1-3亚烷基-(任选取代的8-10元苯并稠合杂环基),-任选取代的C 1-3亚烷基-任选取代的苯基,以及-C 1-3亚烷基-(任选取代的5-10元杂 芳基);其中所述“任选取代的”是指被1、2、3或更多个R 13取代;R 1b不存在;X 1不存在;并且X 4选自C(=O)、S(=O) y、-O-C(=O)-和-NR 10-C(=O)-和-NR 10-S(=O) y-,其中R 10优选地为H或C 1-6亚烷基。
- 权利要求23的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1a为选自下列的基团:任选取代的5、6或7元单环杂环基,任选取代的苯基,以及-任选取代的C 1-3亚烷基-任选取代的苯基;优选地选自下列的基团:任选取代的5、6或7元单环杂环基,任选取代的苯基,以及-C 1-3亚烷基-任选取代的苯基;并且其中所述“任选取代的”是指被1、2、3或更多个R 13取代。
- 权利要求23至25中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13选自:卤素、OH、-NR 11R 12、氰基和C 1-4烷基;以及任选地被1、2或3个独立地选自卤素、OH、-NR 11R 12、氰基和C 1-4烷基的取代基取代的苯基、5、6或7元单环杂环基和5-6元杂芳基,并且其中R 11和R 12各自独立地选自H和C 1-4烷基(优选甲基);
- 权利要求23至27中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 4选自C(=O)、S(=O) y和-O-C(=O)-,并且其中y优选地为2。
- 权利要求20或21的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 4为直接的键。
- 权利要求30的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1a为-C 1-3亚烷基苯基,优选-CH 2-苯基。
- 权利要求22的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:R 1a选自任选地被1、2、3或更多个R 13取代的C 2-6烯基(优选乙烯基、1-丙烯基或2-丙烯基)和C 2-6炔基(优选乙炔基、1-丙炔基或2-丙炔基);并且X 4为C(=O)或-O-C(=O)-。
- 权利要求32的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:R 13选自任选地被1、2或3个独立地选自卤素、OH、氨基、氰基和C 1-4烷基取代的苯基和5-6元杂芳基;优选地,R 13为任选地被1、2或3个独立地选自F、Cl和Br的取代基取代的苯基或吡啶基。
- 权利要求1至9和18至19中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 1为CR 10或N。
- 权利要求35的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、 N-氧化物、同位素标记的化合物、代谢物或前药,其中X 4为直接的键。
- 权利要求35的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 4选自:C(=O)、S(=O) y、-O-C(=O)-、-S-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-或-NR 10-S(=O) y-,优选为C(=O)、-O-C(=O)-或-NR 10-C(=O)-。
- 权利要求35至37中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1b选自H和R 1a,并且优选地,X 1为CH。
- 权利要求36的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:R 1a选自任选地被1、2、3或更多个R 13取代的C 2-6烯基(例如乙烯基、1-丙烯基或2-丙烯基)和C 2-6炔基(例如乙炔基、1-丙炔基或2-丙炔基);和/或R 1b选自任选地被1、2、3或更多个R 13取代的C 1-4烷基。
- 权利要求39的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:R 13选自任选地被1、2或3个独立地选自卤素、OH、氨基、氰基和C 1-4烷基取代的C 1-4烷基、苯基和5-6元杂芳基;优选地,R 13为任选地被1、2或3个独立地选自F、Cl和Br的取代基取代的C 1-4烷基或苯基;更优选地,R 13为C 1-4烷基(例如甲基、乙基、丙基、异丙基或叔丁基)或者任选地被1、2或3个独立地选自F、Cl和Br的取代基取代的苯基。
- 权利要求39至41中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 1为CH或N,优选CH。
- 权利要求37的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:R 1a为选自下列的基团:任选取代的C 3-7环烃基,任选取代的4-7元单环杂环基,任选取代的8-10元苯并稠合杂环基,任选取代的苯基,任选取代的5-10元杂芳基,-任选取代的C 1-3亚烷基-(任选取代的C 3-7环烃基),-任选取代的C 1-3亚烷基-(任选取代的5-7元单环杂环基),-任选取代的C 1-3亚烷基-(任选取代的8-10元苯并稠合杂环基),-任选取代的C 1-3亚烷基-任选取代的苯基,以及-任选取代的C 1-3亚烷基-(任选取代的5-10元杂芳基);优选地,R 1a为选自下列的基团:任选取代的C 3-7环烃基,任选取代的4-7元单环杂环基,任选取代的8-10元苯并稠合杂环基,任选取代的苯基,任选取代的5-10元杂芳基,-C 1-3亚烷基-(任选取代的C 3-7环烃基),-C 1-3亚烷基-(任选取代的5-7元单环杂环基),-C 1-3亚烷基-(任选取代的8-10元苯并稠合杂环基),-C 1-3亚烷基-任选取代的苯基,以及-C 1-3亚烷基-(任选取代的5-10元杂芳基);并且其中所述“任选取代的”是指被1、2、3或更多个R 13取代。
- 权利要求43或44的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13选自:卤素、-OR 11(优选地,R 11为任选地被1、2、3或更多个卤素取代的C 1-6烷基,更优选地为任选地被1、2或3个F或Cl取代的C 1-3烷基)、-NR 11R 12、氰基和C 3-7环烃基,以及任选地被1、2、3或更多个卤素取代的C 1-4烷基、C 2-4烯基和C 2-4炔基,并且其中R 11和R 12各自独立地选自H和C 1-4烷基(优选甲基);优选地,R 13选自:F、Cl、Br、OH、-OC 1-4烷基、-N(C 1-4烷基) 2、氰基、C 3-7环烃基、C 2-4烯基和C 2-4炔基,以及任选地被1、2、3或更多个F、Cl或Br取代的C 1-4烷基;更优选地,R 13选自:F、Cl、Br、-OCH 3、-N(CH 3) 2、氰基、环丙基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、2-丙炔基、甲基、乙基、正丙基、异丙基、叔丁基和CF 3;或者R 13如权利要求9所定义。
- 权利要求43至46中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1b为选自下列的基团:H、 任选取代的C 1-4烷基,任选取代的C 3-7环烃基,任选取代的苯基,-任选取代的C 1-3亚烷基-(任选取代的C 3-7环烃基),以及-任选取代的C 1-3亚烷基-任选取代的苯基;优选地,R 1b为选自下列的基团:H、任选取代的C 1-4烷基,任选取代的C 3-7环烃基,任选取代的苯基,-C 1-3亚烷基-(任选取代的C 3-7环烃基),以及-C 1-3亚烷基-任选取代的苯基;更优选地,R 1b为选自下列的基团:H、苯基;任选取代的C 1-4烷基,所述烷基例如为甲基、乙基或异丙基;任选取代的C 3-7环烃基和-C 1-3亚烷基-(C 3-7环烃基),所述环烃基例如为环丙基、环丁基、环戊基或环己基;以及-C 1-3亚烷基-苯基;并且其中所述“任选取代的”是指被1、2、3或更多个R 13取代;其中R 13优选地选自卤素和C 1-4烷基,更优选地选自F、Cl、Br和甲基。
- 权利要求43至48中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 1为CH或N,优选地为N。
- 权利要求43至49中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 4选自C(=O)和S(=O) y,并且其中y优选为2。
- 权利要求1至51中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:R 2a选自:任选取代的苯基,以及-任选取代的C 1-3亚烷基-任选取代的苯基;优选地,R 2a选自:任选取代的苯基,以及-C 1-3亚烷基-任选取代的苯基;和/或R 2b选自:任选取代的C 1-4烷基,任选取代的苯基,以及-任选取代的C 1-3亚烷基-任选取代的苯基;优选地,R 2b选自:C 1-4烷基,任选取代的苯基,以及-C 1-3亚烷基-任选取代的苯基;其中所述“任选取代的”是指被1、2、3或更多个R 13取代。
- 权利要求52的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13选自卤素和-OR 11,并且其中R 11选自C 1-4烷基(优选甲基);优选地,R 13选自F、Cl、Br和-OCH 3。
- 权利要求1至9中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R为:其中R 1a为选自下列的基团,所述基团任选地被1、2、3或更多个R 13取代:C 1-6烷基,C 2-6烯基,C 2-6炔基,C 5-7环烃基,5、6或7元单环杂环基,8-10元苯并稠合杂环基,苯基,5-6元杂芳基,-C 1-3亚烷基-C 3-7环烃基,-C 1-3亚烷基-(5-7元单环杂环基),-C 1-3亚烷基苯基以及-C 1-3亚烷基-(5-6元杂芳基);R 1b与X 1一起形成二价C 5-7环烃基,或者5、6或7元二价单环杂环基;并且X 4选自C(=O)和S(=O) y。
- 权利要求18至22、35至38、56至57中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13选自:C 1-4烷基-O-;卤素(其包括F、Cl、Br和I);以及任选地被1、2或3个独立地选自卤素的取代基取代的C 1-4烷基或苯基。
- 权利要求10至12、14至16、18至24、26、31至33、39至40、43、45、47、52至53、56和58中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:所述烷基选自:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、 异戊基、新戊基、1-己基、1-庚基和1-辛基;所述烯基选自:乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基和2-己烯基;所述炔基选自:乙炔基、1-丙炔基、2-丙炔基、2-丁炔基、3-丁炔基、2-戊炔基、3-戊炔基、4-戊炔基、2-己炔基和3-己炔基;所述-C 1-3亚烷基苯基选自苯甲基以及苯乙基;所述环烃基选自:环丙基、环丁基、环戊基、环己基或环庚基;所述单环杂环基选自:四氢呋喃基、四氢噻吩基、吡咯烷基(例如吡咯烷-1-基)、噁唑烷基、噻唑烷基、咪唑烷基、1,3-二氧杂环戊烷基、1,3-氧硫杂环戊烷基、哌啶基、哌嗪基、吗啉基(例如吗啉代))、硫代吗啉基、四氢-2H-吡喃基、四氢-2H-噻喃基、1,3-噁嗪烷基(1,3-oxazinane)、1,3-噻嗪烷基(1,3-thiazinane)、六氢嘧啶基、1,3-氧硫杂环己烷基(1,3-oxathiane)、1,4-氧硫杂环己烷基(1,4-oxathiane)、1,3-二氮杂环庚烷基(1,3-diazepane)、1,4-二氮杂环庚烷基(1,4-diazepane)、1,3-氧杂氮杂环庚烷基(1,3-oxazepane)、1,3-硫杂氮杂环庚烷基(1,3-thiazepane);所述杂芳基选自:噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基(例如1-吡唑基、3-吡唑基、4-吡唑基、5-吡唑基)、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基和三嗪基;和/或
- 权利要求1至9中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中Y为:单键、NR 10、O、S、亚甲基、亚乙基、-CH 2-O-、-O-CH 2-、-CH 2-S-、-S-CH 2-、-CH 2-NR 10-、-NR 10-CH 2-、-CH=CH-、-CH=N-或-N=CH-。
- 权利要求1至9和61中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 1a和R 1b与它们所连接的X 1一起形成的所述任选取代的包含3个或更多个环的饱和或部分不饱和稠环体系具有以下式(a)的结构:其中:环A和环B各自独立地为C 3-10环烃基、3-10元杂环基、C 6-10芳基或5-14元杂芳基,优选为C 5-7环烃基(例如环戊基或环己基)、5-7元单环杂环基、苯基或5-6元杂芳基;优选地,所述稠环体系具有式(1)或式(2)的结构:其中R 5a、R 5b在每次出现时各自独立地为R 10;R 7不存在或为R 10;并且m和n在每次出现时各自独立地为0、1、2或3。
- 权利要求1至9和61至62中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 1为CH或N。
- 权利要求1至9中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R为:X 6选自O、S、NR 10、-C(=O)-NR 10-和-S(=O) y-NR 10-,优选地选自:O、S、NH、N(C 1-6烷基)、-C(=O)-NH-、-C(=O)-N(C 1-6烷基)-、-S(=O) y-NH-和-S(=O) y-N(C 1-6烷基)-,更优选地选自:O、S、NH、N(C 1-4烷基)和-C(=O)-NH-,甚至更优选地选自:O、S、NH、N(CH 3)和-C(=O)-NH-;和/或R 9选自:H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 5-7环烃基、5-7元单环杂环基、苯基、5-6元杂芳基和苯基-C 1-6亚烷基-,优选地选自:H、C 1-4烷基(其包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基)、C 2-4烯基(其包括乙烯基、1-丙烯基、2-丙烯基、2-丁烯基和3-丁烯基)C 2-4炔基(其包括乙炔基、1-丙炔基、2-丙炔基、2-丁炔基、3-丁炔基)、苯基和苯基-C 1-4亚烷基-(其包括苯基-亚甲基-和苯基-亚乙基-);上述烷基、亚烷基、烯基、炔基、环烃基、杂环基、苯基和杂芳基任选地被1、2、3或更多个R 13取代;R 13如权利要求1至9中任一项所定义;优选地,R 13在每次出现时独立地选自:卤素(其包括F、Cl、Br和I);OH;氨基;氰基;硝基;以及任选地被1、2、3或更多个独立地选自卤素(其包括F、Cl、Br和I)、OH、氨基、氰基、硝基和苯基的取代基取代的C 1-6烷基(包括C 1-4烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基)和C 6-10芳基(例如苯基)。
- 权利要求65的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 9为苯基-C 1-4亚烷基-。
- 权利要求65至67中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 6选自O和S,优选为O。
- 权利要求65至68中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型 物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 3为CH。
- 权利要求1至51和56至69中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 2a、R 2b与它们所连接的X 2一起形成选自下列的基团,所述基团任选地被1、2、3或更多个R 13取代:C 5-7环烃基;5、6或7元单环杂环基;苯基;以及5-6元杂芳基;并且X 5为直接的键。
- 权利要求70的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13是任选地被1、2或3个独立地选自C 1-4烷基和苯基的取代基取代的C 1-4烷基或苯基-C 1-4烷基-。
- 权利要求1至51和56至69中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 2a为选自下列的基团,所述基团任选地被1、2、3或更多个R 13取代:C 1-6烷基,C 2-6烯基,C 2-6炔基,C 5-7环烃基,5、6或7元单环杂环基,8-10元苯并稠合杂环基,苯基,5-6元杂芳基,-C 1-3亚烷基-C 3-7环烃基,-C 1-3亚烷基-(5-7元单环杂环基),-C 1-3亚烷基苯基以及-C 1-3亚烷基-(5-6元杂芳基);并且R 2b不存在或者选自H和R 2a。
- 权利要求1至51、56至69和72中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 2b不存在,且X 2不存在。
- 权利要求73的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 5选自:C(=O)、S(=O) y、-O-C(=O)-、-S-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-和-NR 10-S(=O) y-,优选为C(=O)、-O-C(=O)-或-NR 10-C(=O)-。
- 权利要求70至74中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 2a为选自下列的基团:任选取代的5、6或7元单环杂环基,任选取代的苯基,以及-任选取代的C 1-3亚烷基-任选取代的苯基,其中任选存在的取代基是1、2、3或更多个R 13;R 2b不存在;X 2不存在;并且X 5选自C(=O)、S(=O) y、-O-C(=O)-和-NR 10-C(=O)-和-NR 10-S(=O) y-,其中R 10优选地为H或C 1-6亚烷基。
- 权利要求1至69和72中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 2为CR 10或N,并且其中R 10优选地为H、OH或C 1-4烷基(例如甲基)。
- 权利要求76的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 5为直接的键。
- 权利要求76的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 5为选自:C(=O)、S(=O) y、-O-C(=O)-、-S-C(=O)-、-O-S(=O) y-、-NR 10-C(=O)-或-NR 10-S(=O) y-,优选为C(=O)、-O-C(=O)-或-NR 10-C(=O)-。
- 权利要求76至78中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 2b选自H和R 2a,并且优选地,X 2为CH。
- 权利要求1至51和56至69中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、 多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 2a为选自下列的基团,所述基团任选地被1、2、3或更多个R 13取代:C 1-6烷基,C 2-6烯基,C 2-6炔基,C 5-7环烃基,5、6或7元单环杂环基,8-10元苯并稠合杂环基,苯基,5-6元杂芳基,-C 1-3亚烷基-C 3-7环烃基,-C 1-3亚烷基-(5-7元单环杂环基),-C 1-3亚烷基苯基以及-C 1-3亚烷基-(5-6元杂芳基);R 2b与X 2一起形成二价C 5-7环烃基,或者5、6或7元二价单环杂环基;并且X 5选自C(=O)和S(=O) y。
- 权利要求72至80中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 13选自:C 1-4烷基-O-;卤素(其包括F、Cl、Br和I);以及任选地被1、2或3个独立地选自卤素的取代基取代的C 1-4烷基或苯基。
- 权利要求70至81中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中:所述烷基选自:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、1-己基、1-庚基和1-辛基;所述烯基选自:乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基和2-己烯基;所述炔基选自:乙炔基、1-丙炔基、2-丙炔基、2-丁炔基、3-丁炔基、2-戊炔基、3-戊炔基、4-戊炔基、2-己炔基和3-己炔基;所述环烃基选自:环丙基、环丁基、环戊基、环己基或环庚基;所述单环杂环基选自:四氢呋喃基、四氢噻吩基、吡咯烷基(例如吡咯烷-1-基)、噁唑烷基、噻唑烷基、咪唑烷基、1,3-二氧杂环戊烷基、1,3-氧硫杂环戊烷基、哌啶基、哌嗪基、吗啉基(例如吗啉代))、硫代吗啉基、四氢-2H-吡喃基、四氢-2H-噻喃基、1,3-噁嗪烷基(1,3-oxazinane)、1,3-噻嗪烷基(1,3-thiazinane)、六氢嘧啶基、1,3-氧硫杂环己烷基(1,3-oxathiane)、1,4-氧硫杂环己烷基(1,4-oxathiane)、1,3-二氮杂环庚烷基(1,3-diazepane)、1,4-二氮杂环庚烷基(1,4-diazepane)、1,3-氧杂氮杂环庚烷基(1,3-oxazepane)、1,3-硫杂氮杂环庚烷基(1,3-thiazepane);所述杂芳基选自:噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基(例如1-吡唑基、3-吡唑基、4-吡唑基、5-吡唑基)、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基和三嗪基;所述-C 1-3亚烷基苯基选自苯甲基以及苯乙基。
- 权利要求1至51和56至69中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中Z为:单键、NR 10、O、S、亚甲基、亚乙基、-CH 2-O-、-O-CH 2-、-CH 2-S-、-S-CH 2-、-CH 2-NR 10-、-NR 10-CH 2-、-CH=CH-、-CH=N-或-N=CH-。
- 权利要求1至51、56至69和84中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中R 2a和R 2b与它们所连接的X 2一起形成的任选取代的包含3个或更多个环的饱和或部分不饱和稠环体系具有以下式(b)的结构:其中:环C和环D各自独立地为C 3-10环烃基、3-10元杂环基、C 6-10芳基或5-14元杂芳基,优选为C 5-7环烃基、5-7元单环杂环基、苯基或5-6元杂芳基;优选地,所述稠环体系具有式(3)或式(4)的结构:其中R 6a和R 6b在每次出现时各自独立地为R 10;R 8不存在或为R 10;并且p和q在每次出现时各自独立地为0、1、2或3。
- 权利要求1至69和84至85中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,其中X 2在每次出现时独立地为CR 10或N,并且其中R 10为H、OH、氨基或C 1-4烷基(例如甲基)。
- 药物组合物,其包含预防或治疗有效量的权利要求1至89中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药,以及药学上可接受的载体,所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
- 权利要求1至89中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者权利要求90的药物组合物在制备用作血管紧张素II 2型(AT 2)受体抑制剂,优选选择性AT 2受体抑制剂的药物中的用途。
- 权利要求91的用途,其中所述药物用于预防或治疗AT 2受体介导的病症或与其相关的症状,所述病症选自:脑血管病症(其包括脑血管痉挛和脑缺血);认知功能障碍(其包括遗忘症、老年性痴呆、艾滋病相关性痴呆和唐氏综合征);中枢神经系统疾病或病症(其包括成瘾如酒精中毒、焦虑、抑郁症或心境恶劣障碍、癫痫、活动过度、疼痛、帕金森病、精神病、睡眠障碍、不规则植物神经功能和迟发性运动障碍、精神分裂症、脱髓鞘疾病如多发性硬化症和肌萎缩性侧索硬化症);呼吸系统疾病(其包括支气管痉挛、哮喘和慢性阻塞性气道疾病);神经元肿瘤;炎性疾病(其包括炎性肠病和骨关节炎);胃肠道(GI)疾病或病症(其包括溃疡性结肠炎、克罗恩病和失禁);由血管舒张引起的血流障碍;过敏性疾病(其包括过敏如湿疹、鼻炎和接触性皮炎);血管痉挛性疾病(包括心绞痛、偏头痛和雷诺氏病);纤维和胶原病(其包括硬皮病和嗜酸性片吸虫病);反射性交感神经营养障碍(其包括肩手综合征);应激相关性躯体障碍;周围神经病变;神经痛;自身免疫性疾病(其包括系统性红斑狼疮、类风湿性关节炎、牛皮癣和移植物抗宿主病);以及风湿性疾病(其包括纤维组织炎)。
- 权利要求91的用途,其中所述药物用于预防或治疗AT 2受体介导的病症或与其相关的症状,所述病症选自:神经病变性病症(包括原发性神经病变和继发性神经病变,例如外周神经病变)或与其相关的症状(包括感觉过敏、痛觉过敏、异常性疼痛、自发性灼痛、麻木、衰弱、灼痛、射痛(shooting pain)和反射丧失),优选神经性疼痛;其中所述继发性神经病变包括:糖尿病性神经病变;带状疱疹相关神经病;尿毒症相关神经病;淀粉样变性神经病;HIV感觉神经病;遗传性运动和感觉神经病;遗传性感觉神经病变;遗传性感觉和自主神经病;伴有溃疡损毁的遗传性神经病;呋喃妥因神经病;腊肠样肿胀神经病;由营养缺乏引起的神经病;由肾衰竭引起的神经病和复杂区域疼痛综合征;由重复活动(如打字或在装配线上工作)引起的神经病变;由抗反转录病毒药物(例如扎西他滨和去羟肌苷)、抗生素(例如甲硝唑和异烟肼)、金化合物、化疗药物(例如长春新碱)、醇、铅、砷、汞和有机磷酸酯杀虫剂引起的外周神经病变;与感染过程相关的外周神经病变(如吉兰-巴雷综合征);特征在于神经元超敏性的病症,其包括痛觉过敏病状,如纤维肌痛、肠易激综合征;与神经再生异常相关的病症,其包括神经元超敏性、乳房疼痛、间质性膀胱炎、外阴痛、癌症化学疗法诱发的神经病变;炎症性疼痛,其可归因于特征在于炎症的病症(包括灼伤,如化学、摩擦或热灼伤;自体免疫性疾病,如类风湿性关节炎;炎症性肠病,如克罗恩氏病和结肠炎;骨关节炎、心脏炎、皮炎、肌炎、神经炎和胶原蛋白血管疾病);神经传导速度受损,其可与如上所述的神经病变性病症(如外周神经病)以及腕管综合征、尺骨神经病变、吉兰-巴雷综合征、面肩胛肱骨肌肉萎缩和椎间盘突出相关;细胞增生性病症,其包括癌症(包括白血病、黑素瘤、前列腺癌、乳癌、卵巢癌、基底细胞癌、鳞状细胞癌、肉瘤、纤维肉瘤、结肠癌、肺癌);以及非癌性增生性病症(包括皮肤病症,如疣、疤 痕疙瘩、牛皮癣、疤病症以及疤痕组织减少和美容重塑);与骨再吸收与骨形成之间的不平衡相关的病症,包括骨质疏松。
- 权利要求1至89中任一项的化合物或者其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者权利要求90的药物组合物在制备用于调节有此需要的女性患者中与AT 2受体相关的生殖功能(其包括月经周期、生育力和发情周期的激素平衡)的药物中的用途。
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